Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information
No relevant information; for further information see IUCLID section 12 "literature search".
Effect on fertility: via oral route
Quality of whole database:
Only a screening test with barium dichloride dihydrate is available. However, based on this study there are no indications of a substantial impairment of fertility in rats up to the highest dose tested. Thus, the NOAEL was 4000 ppm (to average doses of 201.5 and 179.5 mg Ba/kg bw/d to male and and female rats, respectively). No-observed-adverse-effect levels (NOAELs) on developmental toxicity for rats of 4000 ppm were derived. However, this NOAEL is of limited value to evaluate the potential for barium to induce developmental effects because there was no exposure of the females during gestation. Nevertheless, a decision on the registrant’s testing proposal for a study investigating the effects on fertility for barium dichloride dehydrate has not yet been taken by ECHA.

Study performance on sulfides is not considered to be required. For detailed information please refer to endpoint “toxicity to reproduction” data waiving for barium sulfide.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

READ ACROSS CONCEPT

Valid reproduction toxicity studies for barium sulfide are not available. Therefore, because of the lack of appropriate experimental data, read-across from studies with H2S and BaCl2is proposed based on the following reasoning:

 

Read-across to H2S:

The readily water-soluble compound barium sulfide will initially dissociate upon dissolution in water and/or relevant physiological media into barium and sulfide ions.

 

However, sulfide anions will react with water in a pH-dependant reverse dissociation to form hydrogensulfide anions (HS-) or H2S, respectively, according to the following equation:

 

H2S  ↔  H+  +  HS-  ↔  2H+  +  S2-

 

The dissociation behaviour is presented in the Hägg graph reported under IUCLID section 5.1.2 Hydrolysis.

 

The pKa values for the first and second dissociation steps of H2S are 7.0 and 12.9 (for details, refer to the IUCLID section on dissociation constant), respectively. Therefore, at neutral physiological pH values, hydrogen sulfide in the non-dissociated form (H2S) and the hydrogen sulfide anion (HS-) will be present in almost equimolar proportion, whereas only very small amounts of the sulfide anion (S2-) will be present. Conversely, at gastric pH (pH 1-2), non-dissociated H2S will be the predominant species.

 

In conclusion, under physiological conditions, inorganic sulfides or hydrogensulfides as well as H2S will dissociate to the respective species relevant to the pH of the physiological medium, irrespective of the nature of the “sulfide”, which is why read-across between these substances and H2S is considered to be appropriate without any restrictions for the purpose of hazard and risk assessment of barium sulfide.

 

 

Read-across to Ba(OH)2 and BaCl2, respectively:

 

Upon dissolution in water and/or physiological media, dissociation of barium sulfide to release Ba2+ions may initially be expected.

 

However, based on the established fact that barium ions may form poorly soluble species for example with physiologically present carbonate ions, the bioaccessibility/bioavailability may vary between different physiological conditions. Notwithstanding this limitation, it is considered justified to read-across from available data either on barium hydroxide (similar water solubility) and/or barium chloride (higher water solubility), the latter representing a conservative approach). In this context, the water solubility of a substance is used as a first approximation of bioavailability:

 

- barium chloride is highly water soluble with ca. 375 g/L at 20 °C/pH ca. 6.5 (510.4 g/L at pH 1.5)

- barium hydroxide is also highly water soluble (37.4 g/L at 20 °C/pH > 13).

 

In comparison, the water solubility of barium sulfide is 73.5 g/L at 20 °C (pH 13.7; saturated solution).

 

In conclusion, read across from barium chloride and barium hydroxide to barium sulfide is considered as justified since the toxicity of these substances may reasonably be considered to be determined by the availability of barium cations. It is noted that although BaS is a strong base, substantial neutralisation in the gastrointestinal tract at pH-levels of approx. 1.5 – 2 may nevertheless be anticipated.

Conclusion on the study conducted with BaCl2*2H2O:

Only two studies (NTP and Dietz) exist in which a dose-response relationship of different adverse effects on fertility after oral administration of barium chloride was investigated. These studies (see IUCLID section 7.8.1) which were published in peer-reviewed journals were examined with respect to their adequacy for the derivation of NOAEL/LOAEL values for fertility impairment.

Based on these limited investigations with barium chloride as described above, a lack of fully, guideline conform data must be noted. Tentatively, the premating study by Dietz et al. (1992) on rats and mice may be considered as the only acceptable study for the derivation of a preliminary NOAEL for fertility effects of soluble barium compounds. This study investigated the occurrence of different adverse effects in male and female rats and mice and their offspring related to barium chloride exposure via drinking water. A tentative NOAEL for fertility impairment of 4,000 ppm in rats and 2,000 ppm in mice can be derived (see IUCLID endpoint summary 7.8 "short description of key information").

 

For this reason, a testing proposal for a study investigating the effects on fertility was included into the registration dossier of barium dichloride but a final decision has not yet been taken by ECHA.

Conclusion on the study conducted with H2S:

Performance of further reproductive toxicity studies (e.g. a two generation study) is not considered to be required for the following reasons:

- The DNEL derived for local effects would be lower than for effects on reproduction and development, and thus the derived DNELlocal is regarded as protective enough for both endpoints.

- The available data indicating major effects resulting from local toxicity, and thus, from an animal welfare point of view, it appears to be not feasible to investigate reproductive toxicity in a dose range which would be sufficient high to cause reproductive effects, but would be acceptable for the animals, due to the irritating properties of the test compounds.

- It appears not appropriate to conduct animal studies, because of the alkaline pH in aquatic media (corrosive potential).

- In addition, there is sufficient information available (see below) from a fertility and developmental toxicity study in combination with a repeated dose toxicity study to rule out the reproductive system as target organ of toxicity.

Based on the lack of any effects on reproductive performance and organs up to the highest dose (NOAEC, H2S = 80 ppm), the reproductive tract is not considered to represent a target organ of toxicity for hydrogen sulfide. Thus, further testing in a two-generation reproduction toxicity study according to OECD guideline 416 is not regarded to be required for sodium sulfide, since read-across from H2S to Na2S is proposed.

Due to expert judgment the fertility and developmental neurotoxicity screening study, similar to OECD guideline 421, reported by Dorman et al. (2000) with the test substance H2S together with the information from subchronic inhalation toxicity studies in Sprague-Dawley rats, Fisher rats and B6C3F1 mice reported by Morgan et al. (1983) and re-evaluated by Dorman in 2004 can be regarded as adequate to fulfil the REACH-requirements for the endpoint "Toxicity to reproduction".

In the reproduction screening assay, female Sprague-Dawley rats were exposed by inhalation (6h/d, 7d/wk) to concentrations up to 80 ppm H2S during the pre-mating (2 weeks) and mating (2 weeks) periods, during gestation (day 0-19) and post partum (5-18). Males were exposed for a total of 70 days starting 2 weeks before mating. The results did not indicate effects on reproductive performance. There were no effects of exposure on mating and fertility indices, post implantation loss and number of late resorptions or still births. The number of females with live pups, litter size, average length of gestation and the average number of implants per female were not different between exposed and control rats. Examination of testis did not indicate affects of sperm production or sperm morphology. Histopathological investigations did not reveal any changes in the reproductive organs of male and female animals.

In the subchronic toxicity studies (Morgan et al. (1983), re-evaluated by Dorman in 2004, see IUCLID section 7.5 Repeated dose toxicity), rats and mice were exposed by inhalation to similar concentrations of H2S (6h/d, 5d/wk) for 90 days. In these studies, gross pathology and organ weight analysis did not indicate exposure related effects on ovaries and testis, and no lesions were observed by histopathological examinations in non-respiratory tissues. Although details on histopathological evaluations of non-respiratory tissues are not presented in detail the re-evaluated study report (Dorman et al. 2004), the statement on the lack of any effects on non-respiratory tissues can be judged as reliable based on the overall high quality of the study. Major effects of inhalation exposure are local effects in the respiratory tract (olfactory neuronal loss) already occurring at a dose level of 30 ppm. The highest dose level of 80 ppm represents a NOAEC for systemic effects. The original study report from Morgan et al. 1983 is only available as an abstract.


Short description of key information:
Screening study with barium dichloride dihydrate:
Fertility impairment in female rats: NOAEL of 179.5 mg Ba2+/kg bw/d; relates to 221 mg Barium sulfide/kg bw/day (Dietz et al., 1992)
Fertility impairment in male rats: NOAEL of 201.5 mg Ba2+/kg bw/d; relates to 249 mg Barium sulfide/kg bw/day (Dietz et al., 1992)

Effects on developmental toxicity

Description of key information
Developmental toxicity: a NOAEL of >=69.4 mg BaS/kg was derived in an oral developmental toxicity with barium dichloride dihydrate study according to OECD 414.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
69.4 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The study is fully acceptable. Read across is fully justified.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

READ ACROSS CONCEPT

Valid toxicological data on sub-acute or sub-chronic exposure specifically for barium sulfide from animal studies are not available. Therefore, because of the lack of appropriate experimental data, read-across from studies with H2S and BaCl2is proposed based on the following reasoning:

 

Read-across to H2S:

The readily water-soluble compound barium sulfide will initially dissociate upon dissolution in water and/or relevant physiological media into barium and sulfide ions.

 

However, sulfide anions will react with water in a pH-dependant reverse dissociation to form hydrogensulfide anions (HS-) or H2S, respectively, according to the following equation:

 

H2S  ↔  H+  +  HS-  ↔  2H+  +  S2-

 

The dissociation behaviour is presented in the Hägg graph reported under IUCLID section 5.1.2 Hydrolysis.

 

The pKa values for the first and second dissociation steps of H2S are 7.0 and 12.9 (for details, refer to the IUCLID section on dissociation constant), respectively. Therefore, at neutral physiological pH values, hydrogen sulfide in the non-dissociated form (H2S) and the hydrogen sulfide anion (HS-) will be present in almost equimolar proportion, whereas only very small amounts of the sulfide anion (S2-) will be present. Conversely, at gastric pH (pH 1-2), non-dissociated H2S will be the predominant species.

 

In conclusion, under physiological conditions, inorganic sulfides or hydrogensulfides as well as H2S will dissociate to the respective species relevant to the pH of the physiological medium, irrespective of the nature of the “sulfide”, which is why read-across between these substances and H2S is considered to be appropriate without any restrictions for the purpose of hazard and risk assessment of barium sulfide.

 

 

Read-across to Ba(OH)2 and BaCl2, respectively:

 

Upon dissolution in water and/or physiological media, dissociation of barium sulfide to release Ba2+ions may initially be expected.

 

However, based on the established fact that barium ions may form poorly soluble species for example with physiologically present carbonate ions, the bioaccessibility/bioavailability may vary between different physiological conditions. Notwithstanding this limitation, it is considered justified to read-across from available data either on barium hydroxide (similar water solubility) and/or barium chloride (higher water solubility), the latter representing a conservative approach). In this context, the water solubility of a substance is used as a first approximation of bioavailability:

 

- barium chloride is highly water soluble with ca. 375 g/L at 20 °C/pH ca. 6.5 (510.4 g/L at pH 1.5)

- barium hydroxide is also highly water soluble (37.4 g/L at 20 °C/pH > 13).

 

In comparison, the water solubility of barium sulfide is 73.5 g/L at 20 °C (pH 13.7; saturated solution).

 

In conclusion, read across from barium chloride and barium hydroxide to barium sulfide is considered as justified since the toxicity of these substances may reasonably be considered to be determined by the availability of barium cations. It is noted that although BaS is a strong base, substantial neutralisation in the gastrointestinal tract at pH-levels of approx. 1.5 – 2 may nevertheless be anticipated.

Data BaCl2:

Developmental toxicity of barium chloride dihydrate was evaluated in a recent prenatal developmental toxicity study by daily administration of the test item at dose levels of 0, 10, 30 or 100 mg BaCl2 * 2 H2O/kg body weight to pregnant rats from gestation day 1 up to and including gestation day 20. No effects on body weights, food consumption and clinical signs were observed. Maternal toxicity was evidenced by the spontaneous deaths of two animals on gestation day 21 only and the conditional decline of another animal on gestation day 21 in the high dose group (100 mg BaCl2 * 2 H2O/kg bw).

No developmental toxicity or treatment-related observations, whatsoever in external, visceral and skeletal foetal examinations were observed in any dose level.

The NOAEL for maternal toxicity was therefore 30 mg/kg body weight barium chloride dihydrate (25.6 mg/kg bw barium chloride)). In absence of developmental effects, the NOAEL for prenatal developmental toxicity in the rat was ≥ 100 mg/kg body weight barium chloride dihydrate (≥85.3 mg/kg bw barium chloride).

Furthermore, tentative NOAEL values for developmental toxicity of 4,000 ppm and 2,000 ppm for rats and mice, respectively, are also reported in the study by Dietz et al. (1992). However, these NOAELs are of limited value to evaluate the potential for barium to induce developmental effects because the study design did not include prenatal exposure of the female animals to barium dichloride dihydrate. Therefore, this study has to be considered as inadequate for the assessment of the potential to induce developmental toxicity and cannot be used in a regulatory context.

Data Na2S:

Performance of further developmental toxicity / teratogenicty studies (e.g. a prenatal developmental study) is not considered to be required for the following reasons:

- The DNEL derived for local effects would be lower than for effects on reproduction and development, and thus the derived DNELlocal is regarded as protective enough for both endpoints.

- The available data indicating major effects resulting from local toxicity, and thus, from an animal welfare point of view, it appears to be not feasible to investigate reproductive toxicity in a dose range which would be sufficient high to cause reproductive effects, but would be acceptable for the animals, due to the irritating properties of the test compounds.

- It appears not appropriate to conduct animal studies, because of the alkaline pH in aquatic media (corrosive potential).

- In addition, there is sufficient information available (see below) from a fertility and developmental toxicity study in combination with a repeated dose toxicity study to rule out the reproductive system as target organ of toxicity.

No indications of a teratogenic potential of H2S were observed up to the highest dose in the available and reliable studies. Thus, further testing in prenatal developmental toxicity studies according to OECD guideline 414 is not considered necessary for sodium sulfide, since read-across from H2S to Na2S is proposed.

 

Due to expert judgment the fertility and developmental neurotoxicity screening study, similar to OECD guideline 421, reported by Dorman et al. (2000) with the test substance H2S can be regarded as adequate to fulfil the REACH-requirements for the endpoint “Developmental toxicity / teratogenicity”.

In the reproduction screening assay, female Sprague-Dawley rats were exposed by inhalation (6h/d, 7d/wk) to concentrations up to 80 ppm H2S during the pre-mating (2 weeks) and mating (2 weeks) periods, during gestation (day 0-19) and post partum (5-18). Males were exposed for a total of 70 days starting 2 weeks before mating. The F1 offspring generation was examined extensively for occurrence of external defects post partum and for developmental landmarks (pinnae detachment, surface righting, incisor eruption, negative geotaxis, eyelid separation, vaginal patency, preputial separation) and developmental neurotoxicity (motor activity, passive avoidance, FOB, acoustic startle) during the postnatal period. Gross macroscopic examination and organ weight analysis were conducted on all F1 offspring upon necropsy on PND 63 +/- 3, and histopathological examinations of the brains of control and high dose animals was done. In addition, neuropathology was conducted in selected weanling rats and adult offspring. The results of this study did not indicate effects of treatment on the in-uteri and postnatal development of offspring from parents exposed continuously including the phase of organogenesis. Thus, a NOAEC of 80 ppm hydrogen sulfide (ca. 111 mg H2S/m3 air at 25 °C) may be derived from the screening study for developmental toxicity in rats.

In addition, findings of further supporting studies with pre- and postnatal exposure of rats and pups to H2S are not contradictory (Hayden, 1990; Skranjny, 1992). However, the relevance of the finding on neuronal transmitter levels (Skranjny, 1992) in the brain of offspring from rats exposed during gestation to 20 and 75 ppm H2S is on the development of offspring is questionable in light of the lack of any effects on behavioral neurotoxicity and developmental landmarks in the extended study reported by Dorman et al.( 2000).

 


Justification for selection of Effect on developmental toxicity: via oral route:
Barium dichloride dihydrate was evaluated recently in a GLP compliant oral prenatal toxicity study according to OECD guideline 414. The NOAEL is reported as re-calculated barium sulfide.

Justification for classification or non-classification

No classification is required based on the results of the prenatal developmental toxicity study. Further classification and labelling will be postponed till the results of the study investigating the effects on fertility with barium dichloride dihydrate are available.

Additional information